Efficacy of Early Health Intervention Programs on Adverse Effects of Chemotherapy Among Women With Breast Cancer: A Randomized Controlled Trial

Aim Breast cancer is the most frequently diagnosed cancer and the primary cause of cancer-related mortality among women. Advances in medical science have led to chemotherapy drugs that significantly reduce cancer mortality and increase patient’s life expectancy. However, the systemic nature of chemotherapy leads to a wide range of physical and psychosocial challenges. Chemotherapy is usually given on an outpatient basis and hence patients have to manage treatment-related symptoms at home. This study aimed to evaluate the efficacy of early health intervention programs, specifically health education and progressive muscle relaxation, in managing the adverse effects of chemotherapy among women with breast cancer. Methods A randomized controlled trial was carried out at the chemotherapy unit of a tertiary care hospital in Thiruvananthapuram, Kerala, India. The research involved 340 female breast cancer patients receiving their initial chemotherapy cycle, divided equally into an experimental group and a control group. Patients in the intervention group received an early health intervention program on the day of their first chemotherapy cycle. These interventions included a 40-minute session comprising health education to manage the adverse effects of chemotherapy at home and a demonstration of progressive muscle relaxation techniques, which must be practiced by the patients two times daily till the end of chemotherapy. Participants in the control group received routine care from the hospital. The primary outcome variable was the adverse effects of chemotherapy. Sociodemographic and clinical information were collected using a structured questionnaire. The severity of adverse effects was assessed using the Common Terminology Criteria for Adverse Events, version 3 (CTCAE v3). Result The average age of participants was 54.7 ± 9.7 years in the control group and 52.4 ± 9 years in the experimental group. The majority in both groups had invasive breast cancer, with 144 (84.7%) in the control group and 153 (90%) in the experimental group. In the post-test, most participants in the control group experienced severe fatigue (136, 80%), mucositis (82, 48.2%), nausea (83, 49.1%), and vomiting (81, 47.6%). Conversely, the majority in the experimental group reported mild mucositis (110, 64.7%), nausea (92, 54.1%), and vomiting (93, 54.7%), along with moderate fatigue (116, 68.2%). Hair loss was incomplete for all participants in the control group and 115 (97.6%) participants in the experimental group. There was a significant difference between the experimental and control groups regarding fatigue (p < 0.001), insomnia (p < 0.01), anorexia (p < 0.01), mucositis (p < 0.01), nausea (p < 0.01), vomiting (p < 0.01), leukopenia (p = 0.001), neutrophil count (p < 0.01), hair loss (p < 0.05), and taste alteration (p < 0.01) during the post-test. Conclusion The study demonstrated that early health interventions, such as health education and progressive muscle relaxation, significantly reduced the adverse effects experienced by breast cancer patients undergoing chemotherapy. This suggests that providing supportive education and exercise training to both patients and caregivers can be beneficial in managing these side effects.

Breast cancer is the most frequently identified cancer among women, and is the primary cause of cancerrelated deaths, after colorectal and lung cancer.In 2020, the GLOBOCAN report recorded 2.3 million cases of breast cancer, accounting for 11.7% of all cancer cases, and 6.85 lakh (6.9%) deaths globally [1].The incidence of cancer in Kerala is increasing, with a 36% rise in new cases, according to the latest State Economic Review -2024.The Regional Cancer Centre (RCC) in Thiruvananthapuram, known as one of the leading cancer care centers in the country, shows an increase from 11,191 cases in 2020-2021 to 15,324 cases in 2022-2023.Data from the population-based cancer registry at RCC indicates a higher prevalence of lung cancer among men and breast cancer among women [2].
The treatment for breast cancer is tailored based on the specific subtype of the disease and the extent of its spread to lymph nodes (stages II or III) or other parts of the body (stage IV) [3].Chemotherapy is the most commonly used treatment, and with advancements in medical science, chemotherapy drugs have reduced cancer mortality and increased the life expectancy of patients.However, due to its systemic nature, chemotherapy can lead to various physical and psychosocial challenges, leading to non-compliance with the treatment [4].Breast cancer patients undergoing chemotherapy usually receive treatment on an outpatient basis, and hence, they have to deal with treatment-related symptoms at home.Previous research highlights that cancer patients need information that is thorough, personalized, and tailored to their needs [5].
Different chemotherapy regimens may result in complications such as nausea, vomiting, hair loss, fatigue, mouth sores, digestive issues, anemia, low platelet count, susceptibility to infections, and imbalances in water and electrolytes, which can weaken patients [6,7].
A qualitative study of breast cancer patients receiving chemotherapy revealed that some patients are hesitant to seek treatment in hospitals due to a fear of hospitalization.Despite being reassured that their hair will grow back after chemotherapy, many patients remain distressed, viewing hair loss as a visible symbol of being a cancer patient undergoing treatment [8].
By practicing self-care, patients can mitigate the severity of side effects and improve their quality of life.Adequate knowledge and motivation are crucial for promoting effective self-care practices [9][10][11][12][13].
Guided imagery (GI) and progressive muscle relaxation (PMR) have been shown to effectively alleviate fatigue and pain, as well as enhance health-related quality of life (HRQoL) in patients receiving chemotherapy [14].
The Radiotherapy Department at Government Medical College, Thiruvananthapuram is well-organized and staffed by expert oncologists and a skilled healthcare team offering free medical services for cancer patients, including diagnosis and treatment.Annually, the department registers over 2,500 new cancer cases, with more than 1,400 patients undergoing chemotherapy each month.Breast cancer is the most prevalent type of cancer treated here.The severity of symptoms varies among these patients, often causing delays in completing chemotherapy as scheduled.
While numerous studies on different strategies to manage the side effects of patients undergoing chemotherapy exist in various countries, data specific to India, particularly Kerala, are scarce.The number of cancer cases and patients receiving chemotherapy in Kerala is rising significantly.So the investigator decided to assess the efficacy of early health intervention programs, which include health education and progressive muscle relaxation to manage the adverse effects of chemotherapy among patients with breast cancer.

Study design and setting
A randomized controlled trial design was adopted for the study.The study comprises an experimental group and a control group.The study protocol was developed in alignment with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013 statement [15] and the CONSORT (Consolidated Standards of Reporting Trials) 2010 statement [16].The study was conducted at the Chemotherapy Unit, Government Medical College Hospital, Thiruvananthapuram, Kerala, India from June 2020 to November 2021.The objective of the study was to assess the efficacy of early health intervention programs on the adverse effects of chemotherapy among patients with breast cancer.The participants in the control group were subjected to routine care from the chemotherapy unit.The participants in the experimental group were subjected to early health intervention programs, which included health education and PMR in addition to routine care.

Study sample and sampling
Based on the findings of an earlier study [17], the sample size for this study was calculated using the following formula: Where σ is the standard deviation and δ is the difference in the mean (type 1 error α = 0.05 and power β = 80%).The required sample size for each group was determined to be 170, taking into account 10% attrition.Thus, the sample size for the study was 340.Female patients aged 18 years or older, who had been clinically diagnosed with breast cancer (stages I, II, or III), had an ECOG (Eastern Cooperative Oncology Group) performance status of 2 or less (indicating they were ambulatory, capable of all self-care, and spent more than half of their waking hours active), and were receiving combination chemotherapy for the first time were included in the study.Patients were excluded if they had previous chemotherapy exposure, were undergoing concurrent radiotherapy, had visual, hearing, or cognitive impairments, or had known psychiatric illnesses.
The sampling technique of the study was block randomization.A computer-generated random allocation sequence, created using Random Allocation Software, was used to produce 85 blocks with a block size of four.For allocation concealment, sequentially numbered, sealed, opaque envelopes were used.Based on this sequence, the researcher prepared 85 sealed, opaque envelopes, each containing assignments for two participants in the experimental group and two in the control group.The allocation process was designed to ensure equal numbers in each group and maintain the unpredictability of group assignments.The envelopes were organized in ascending order according to the randomization sequence.An independent person not involved in the study randomly selected the sealed envelopes and assigned participants to either the experimental or the control group.Patients with breast cancer attending the radiation oncology OPD at Medical College Hospital Trivandrum, who met the eligibility criteria, were enrolled in the study after obtaining written informed consent.
Figure 1 illustrates the CONSORT flow chart for the recruitment of participants in the study.A total of 424 patients were screened for eligibility, of which 340 met the criteria.These 340 participants were then equally randomized into the experimental and control groups.Notably, there were no dropouts throughout the study, and all participants were included in the final analysis.

Intervention
Participants in the control group received the standard care provided by the chemotherapy unit.In contrast, participants in the experimental group received early health intervention programs administered by the investigator in addition to the standard care.The intervention lasted for 40 minutes, which was given on the first day of chemotherapy, and included an educational session and demonstration of the PMR technique.The educational session was conducted using a lecture-discussion format, either individually or in small groups of three to four patients with PowerPoint (Microsoft Corporation, Redmond, WA) and colorful images to provide information on breast cancer chemotherapy, its adverse effects, and measures to manage these adverse effects till the end of scheduled chemotherapy.The session lasted for 20 minutes.Additionally, a pamphlet in Malayalam covering this information was distributed.Jacobson's progressive muscle relaxation (JPMR) technique was demonstrated by the investigator to the patients and their caregivers, using an audio recording for instructions.The demonstration also lasted for 20 minutes.Participants were asked to do a return demonstration and corrections were provided as necessary.Instructions for practicing JPMR at home were also shared via an audio clip sent through WhatsApp.To reinforce the intervention, telephone followups were conducted every other day during the first week, and weekly thereafter.Participants were instructed to perform JPMR exercises in the morning, evening, and whenever they experienced fatigue or nausea till the completion of chemotherapy.

Data collection tools
The data were collected through structured interviews, medical record reviews, and self-reports.

Socio-Demographic and Clinical Characteristics of the Patients
The socio-demographic data encompassed variables such as age, gender, marital status, education, occupation, place of residence, type of family, monthly family income, adverse health habits, and family history of cancer.Clinical data included details on the stage of cancer, type of breast cancer, type of chemotherapy (adjuvant or neoadjuvant), interval between cycles, comorbidities, and ECOG performance status [18].Content validity was done by eight experts.

Common Terminology Criteria for Adverse Events, Version 3 (CTCAE v3.0)
The Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, created by the US National Cancer Institute, serves to classify and grade adverse events (AEs) linked to cancer treatments [19].This terminology is essential for reporting AEs and a severity grade was assigned to each AE term.The grading system in CTCAE version 3.0 ranges from grade 1 to grade 5, with specific clinical descriptions for each severity level: grade 1: mild AE; grade 2: moderate AE; grade 3: severe AE; grade 4: life-threatening or disabling AE; and grade 5: death related to the AE.CTCAE v3 includes a total of 570 AEs.However, in the present study, only 16 AEs were selected based on a literature review.These include anemia, leukopenia, neutropenia, thrombocytopenia, fatigue, insomnia, hair loss, anorexia, constipation, diarrhea, oral mucositis, nausea, vomiting, taste alteration, fever, and pain (myalgia).The tool was translated to the local language, Malayalam, and back-translated to English.Since the tool is an open-access standardized one, psychometric properties were not reassessed.

Outcome measurement
Adverse effects of chemotherapy were the outcome variable of the study and were assessed with CTCAE version 3.0 in both the experimental and control groups when patients reported for their second chemotherapy session.

Ethical consideration
The The investigator provided a detailed explanation of the study and informed written consent was obtained from participants who met the inclusion criteria and agreed to join the study voluntarily.The consent form assured participants that their medical care at the hospital would remain unaffected by their decision to participate or withdraw, and it guaranteed the confidentiality of their data.Socio-demographic and clinical information was gathered from all participants.
Patients were assigned to experimental and control groups through block randomization.A computergenerated random number table, using a block size of four, determined the allocation.Each allocation was recorded, folded, and placed in a sealed opaque envelope.A total of 85 envelopes, numbered from 1 to 85, were prepared and randomly drawn for patient assignment.An independent department member, uninvolved in the study, carried out the allocation.
Participants in the control group received the standard care provided by the chemotherapy unit.In contrast, participants in the experimental group received early health intervention programs administered by the investigator in addition to the standard care.Both patients and their caregivers were seated comfortably in a quiet room in the chemotherapy department before the chemotherapy administration, where the intervention took place.The intervention lasted for 40 minutes and included an educational session and a demonstration of the PMR technique.An additional 10 minutes were allocated at the end of the session for answering questions, and 20 minutes were dedicated to the return demonstration of the PMR technique.
The educational session was conducted using a lecture-discussion format, either individually or in small groups of three to four patients.The session utilized PowerPoint presentations with colorful images to provide information on breast cancer chemotherapy, its adverse effects, and measures to manage these adverse effects.The session lasted 20 minutes.Additionally, a pamphlet in Malayalam covering this information was distributed.The JPMR technique was demonstrated by the investigator to the patients and their caregivers, using an audio recording for instructions.The demonstration also lasted 20 minutes.
Participants were asked to do the return demonstration and corrections were provided as necessary.
Instructions for practicing JPMR at home were also shared via an audio clip sent through WhatsApp.To reinforce the intervention, telephone follow-ups were conducted every other day during the first week, and weekly thereafter.Participants were instructed to perform JPMR exercises in the morning, evening, and whenever they experienced fatigue or nausea.
Participants in both groups received a CTCAE diary detailing 16 possible adverse effects of chemotherapy for breast cancer, with descriptions of their severity levels according to the CTCAE version 3.They were instructed on how to document these side effects at home following chemotherapy.Patients were asked to bring the diary with them after three weeks when they returned for their second cycle of chemotherapy.Those in the experimental group received an additional diary to record their self-care practices and PMR activities to ensure compliance.The investigator's contact number was provided for any necessary clarifications.A post-test was administered when patients returned for their second chemotherapy session, in both the experimental and the control groups.

Statistical analysis
Data were analyzed by descriptive and inferential statistics using SPSS version 25 (IBM Corp., Armonk, NY) [20].The similarity between the groups regarding socio-demographic and clinical variables was evaluated using the chi-square test.The intervention's effectiveness was determined through the Mann-Whitney U test.

Results
A total of 340 women with breast cancer, who were undergoing their initial chemotherapy cycle, took part in the study, with 170 participants in both the experimental and control groups.Table 3 shows that 136 (80%) participants in the control group experienced severe fatigue, whereas the majority of participants in the experimental group (116, 68.2%) had only a moderate level of fatigue.In terms of hair loss, most participants in both groups experienced incomplete hair loss (170 (100%) in the control group and 165 (97.6%) in the experimental group).Additionally, anemia, leukopenia, neutropenia, and thrombocytopenia were mild in the majority of patients in both groups.There was a significant difference between the experimental and control groups in terms of leukopenia (p = 0.001), neutrophil count (p < 0.01), fatigue (p < 0.001), and hair loss (p < 0.05) during the post-test.Early health intervention programs were effective in reducing adverse effects of chemotherapy, such as leukopenia, neutropenia, fatigue, and hair loss.However, no significant difference was found regarding anemia and thrombocytopenia.Z#: Mann-Whitney U test; **: significant at 0.01 level; *: significant at 0.05 level.

Discussion
The present study aimed to evaluate the efficacy of early health intervention programs (health education and PMR) on the adverse effects of chemotherapy among patients with breast cancer.The study's findings indicated a significant difference between the experimental and control groups regarding adverse effects of chemotherapy, such as leukopenia (p = 0.001), neutropenia (p < 0.01), fatigue (p < 0.001), insomnia (p < 0.01), anorexia (p < 0.01), constipation (p < 0.01), mucositis (p < 0.01), nausea (p < 0.01), vomiting (p < 0.01), hair loss (p < 0.05), and taste alteration (p < 0.01) during the post-test.These results demonstrate early health intervention programs effectively managed chemotherapy-related adverse effects in breast cancer patients.Therefore, the research hypothesis, which posited that there would be a significant difference in the severity of adverse effects of chemotherapy between the experimental and control groups after the intervention, is confirmed and can be accepted.
The study's findings align with the results from a randomized clinical trial involving 60 women with breast cancer undergoing chemotherapy, which demonstrated that self-care education significantly reduced mouth sores, nausea, and vomiting [21].
A parallel-group, single-blinded, pilot, quasi-experimental trial of a psychoeducational intervention showed significant differences in fatigue, pain, and sleeping difficulty between the experimental and control groups [22].This is also in agreement with the findings of the present study.
The current study is also backed by a randomized clinical trial that evaluated the effectiveness of GI and PMR in managing a cluster of symptoms experienced by chemotherapy patients [14].The findings indicated that participants in the intervention group experienced significantly lower levels of fatigue and pain compared to the control group.Additionally, symptoms such as nausea, vomiting, and retching were significantly less frequent in the intervention group.While the previous study focused solely on PMR and GI, the present study incorporated both health education and PMR.
A quasi-experimental study conducted at the outpatient clinics of the Oncology Center at Mansoura University Hospital involved 80 women who had undergone mastectomy and were receiving parenteral adjuvant chemotherapy for the first time.The results demonstrated that a self-care educational program significantly reduced chemotherapy side effects such as fatigue, nausea, vomiting, mouth sores, and hair loss in the intervention group compared to the control group [23].These findings are consistent with the results of the present study.In all the previously mentioned studies, either health education or PMR was used alone as the intervention.However, in the current study, the researcher combined both health education and PMR.As a result, significant differences were observed in a greater number of side effects compared to the other studies.In the present study, both groups were comparable in all sociodemographic variables except the family income and occupation.People from different socioeconomic statuses rely upon the Government Medical College Hospital, Thiruvananthapuram for the management of their disease conditions, especially for cancer treatment.That may be the reason for the difference between the groups in terms of occupation and family income, even though the study design was a randomized controlled trial.The strengths of the study include the study's robust design, such as the use of randomization and the control group, as well as the practical implications of the findings for managing the adverse effects of chemotherapy among patients with breast cancer.

Limitation
The study has certain limitations.Firstly, data collection was confined to a single hospital.Although the Government Medical College in Thiruvananthapuram, Kerala, serves patients from various socio-economic backgrounds, the study's scope is restricted to a specific geographic region, which affects the generalizability of the findings.Secondly, using self-reporting tools introduces some bias.It is important to recognize that while self-report measures are common and convenient, they have limitations compared to more objective methods like observation.One such limitation is that self-report measures may have lower validity and honesty, as individuals might provide inaccurate or biased information, either intentionally or unintentionally.

Conclusions
Fatigue was the most common adverse effect of chemotherapy and was severe among the participants in the control group and moderate in the experimental group.The present study aimed to evaluate the efficacy of early health intervention programs, including health education and progressive muscle relaxation, in managing the adverse effects of chemotherapy among women with breast cancer.Results suggest that there was a significant difference in the severity of adverse effects of chemotherapy, such as fatigue, insomnia, anorexia, mucositis, nausea, vomiting, leukopenia, neutrophil count, hair loss, and taste alteration, among patients with breast cancer between experimental and control group after the intervention.The study highlights the need for early recognition of the adverse effects of chemotherapy and encouragement of patient's involvement in their treatment and management of side effects to improve the quality of life.statistical analysis.The author is greatly indebted to the patients who cooperated very well during the data collection.

FIGURE 1 :
FIGURE 1: CONSORT flow chart of recruitment of participants.CONSORT: Consolidated Standards of Reporting Trials.
trial protocol received approval from two ethics committees: the Institutional Human Ethics Committee of Government Medical College, Thiruvananthapuram (approval number: CNT/IEC/47/10/2021), where the study was conducted, and the Institutional Ethics Committee of Sri Ramachandra Institute of Higher Education and Research, Chennai (approval number: IEC-NI/19/NOV/71/88), where the study was registered.Additionally, the trial was registered with the Clinical Trials Registry-India (CTRI/2020/09/028178).The study adhered to ethical guidelines for clinical trials and followed COVID-19 protocols.Each participant received an information sheet and provided informed consent.
(CNT/IEC/47/10/2021 and IEC-NI/19/NOV/71/88). Patients attending the daycare chemotherapy unit for their first cycle of chemotherapy for breast cancer were screened based on the inclusion and exclusion criteria.During the data collection period, all COVID-19 infection control protocols were strictly followed.

Table 1
shows that the mean age of participants was 54.7 ± 9.7 years in the control group and 52.4 ± 9 years in the experimental group.

TABLE 1 : Distribution of participants based on socio-demographic variables.
c 2 : chi-square value.BPL: below poverty line; APL: above poverty line.

Table 2
experiment group).Since the p-values of all variables are above 0.05 for cancer stage, type of cancer, chemotherapy, chemotherapy interval, comorbidities, and ECOG status, there is no statistical difference between the groups, indicating homogeneity across clinical variables.

TABLE 2 : Distribution of participants based on clinical variables.
c2: chi-square value; ECOG: Eastern Cooperative Oncology Group.

Table 5
shows that febrile neutropenia, pain, and numbness were absent in most of the participants, i.e., 131 (77.1%), 99 (58.2%), and 164 (96.5%), respectively, in the control group and 156 (91.8%), 113 (66.5%), and 169 (99.4%), respectively, in the experimental group.There was a significant difference in febrile neutropenia between participants in the experimental and control group (p < 0.01).Early health intervention programs were effective in reducing febrile neutropenia.No significant difference was observed in the case of pain and numbness.